This is a video that documents the experiences of three children who have participated in the pilot study of intranasal ketamine as a treatment for juvenile bipolar disorder.

Dr. Demitri Papolos, Director of Research for JBRF, developed and implemented a pilot study to explore the efficacy of intranasal ketamine as a treatment for children who have been diagnosed with early-onset bipolar disorder. The study is in its fourth year and includes over 20 children and teens who fit the Fear of Harm profile (click here for a description of the Fear of Harm Phenotype) and struggle with thermoregulatory dysfunction (click here to access the study relevant to thermoregulation).

The children and teens participating in this pilot study had symptoms that were resistant to traditional treatment protocols for bipolar disorder.

The Goal

The goal of the Genetics Study is to better understand the genetic basis of juvenile bipolar disorder. Greater comprehension of the biological basis of the disorder will lead to better methods of prevention and treatment.

Genetics 101

The human body is composed of trillions of cells. Each one of these cells contains chromosomes. There are 23 pairs of chromosomes in every cell except for ova and sperm, which have only a single copy. The chromosome pairs are made up of one chromosome inherited from our mother and one inherited from our father, making 46 chromosomes in all.

The chromosomes are made of DNA (deoxyribonucleic acid). Each chromosome consists of two very long thin strands of DNA chains twisted into the shape of a double helix, resembling a twisted ladder.

The rungs on the DNA ladder are called base pairs. There are only 4 types of DNA bases produced in cells, referred to by their shorthand signatures: A, T, G and C. These 4 bases are strung together, chemically, over and over in a precise manner creating a continuous string of 3-billion bases in every cell in every person. This constitutes the human genome. The base pairs are essentially a set of instructions given to cells. The order of the base pairs serves the same purpose as the order of letters on a page – only instead of connecting letters to form words, DNA bases connect and communicate biological information to cells. One is the instruction to make a specific protein, which is guided by a 3-base unit called the genetic code. For example, the 3-base unit ATG instructs the protein synthesizing machinery in a cell to place the amino acid methionine into a growing protein (amino acids are the building blocks of proteins).

Each strand of DNA is really a long string of genes. Each gene contains the code to make one particular protein. Proteins are the building blocks for most of your body. In the same way that a wall is made mostly of bricks, every cell is made mostly of proteins. Even the parts of a cell that are not proteins, such as carbohydrates and fats, are influenced by them; proteins guide their synthesis and destruction.

We inherit one copy of every chromosome from each parent. Consequently, we also inherit, with some exceptions, two copies of every gene, one from each parent. About 99.9% of the genetic code is identical from person to person. The remaining 0.1% is small variations in DNA between people. It is these small variations – having slightly different genes – that make us all different from each other.

Genes are how we inherit features from our ancestors. For example, children usually resemble their parents because they have inherited their parents’ genes. If someone has blue eyes it is the direct result of that person having genes inherited from one or both parents that code for proteins that make their eyes look blue. Another person could have genes that code for proteins that make their eyes look brown. The same is true for all physical characteristics. The different versions of a gene that cause these changes are referred to as alleles.

Another type of information that exists in our genome is determining which genes are active in a particular cell. A different set of genes is active in each cell type creating the extraordinary functional diversity of cells and organs; from skin to brain to eye.

The entire package (genes, DNA, alleles) makes up your genome; a unique personal set of hereditary information handed down from parents, and then transmitted to children.

Genomes change. They can change between generations or over a lifetime. These changes are called mutations, which essentially can create new alleles – new modified versions of genes. A mutation in a gene responsible for skin color, for example, created alleles for dark skin and fair skin color. Mutations happen by chance during the formation of ova and sperm, and most make no difference at all. However, some mutations drive human evolution, like the changes in the genes responsible for brain development that resulted in our capacity for language and abstract thought. Others cause disease, like cystic fibrosis, sickle cell anemia, and bipolar disorder.

Finding the Genes Responsible Bipolar Disorder: GWAS and Sequencing

There are a number of approaches geneticists have developed to identify genes (actually, the mutated versions of normal genes) involved in genetic disorders. The first step, of course, is to find patients and archive their DNA. Over the past few years, the JBRF has been collecting DNA from children with bipolar disorder, and in some cases, their siblings and biological parents.

One approach to finding unknown genes is called GWAS (short for genome-wide association study). In this approach, geneticists analyze the entire genome for a type of variant called a SNP. A million SNPs are analyzed simultaneously using DNA chip technology. This is a collection of microscopic DNA spots attached to a solid surface, a gene chip. Thousands of patients and control subjects are studied with the goal of finding a few SNPs out of the million analyzes that appear more frequently in the patient population compared with controls. These SNPs often (but not always) pinpoint the precise gene involved, but cannot identify the causal mutation. The SNPs themselves do not directly cause the disease; they are simply “tagging along” with the actual causal variants. For this reason, researchers often need to take additional steps, such as sequencing DNA base pairs in that particular region of the genome, to identify the exact genetic change involved in the disease. GWAS has become the method of choice for identifying disease causing genes in complex traits such as bipolar disorder and other neuropsychiatric disorders.

A small part of a DNA microarray – a technique that fluorescently labels and displays DNA – as many as 500,000 SNPs can be compared at the same time.

Research Next Step

Although GWAS is a very powerful tool for identifying genes involved in complex traits, it has serious limitations, the major one of which is that it can only find common alleles that may contribute to disease. Unfortunately, in bipolar disorder and other inherited psychiatric disorders, common variants are only responsible for about 10-20% of the genetic risk. The majority of cases, it is widely believed, are caused by so-called rare variants – mutations that drastically affect gene function that are found in less than ~1% of the population. Hundreds, perhaps thousands of different rare variants are believed to be responsible for bipolar disorder throughout the world. The same principle holds true for schizophrenia and autism. Collectively, these rare variants are responsible for the overwhelming majority cases. One type of rare variant known to be responsible for ~10-20% of schizophrenia and autism is the so-called copy number variant (CNV), which results in a loss or gain of one or several genes. CNVs can cause bipolar disorder as well, but it’s less common than in these other conditions. The only way to identify rare variants responsible for the overwhelming majority of bipolar disorder (and schizophrenia and autism as well) is to sequence the DNA of affected individuals. There are two fundamental approaches, both of which will be undertaken by JBRF: exome sequencing and whole genome sequencing.

Exome sequencing essentially determines every letter in a DNA sequence for the portion of the genome called exons. Exons are the parts of a gene that provide instructions for protein production. Despite their key role in cells, exons only represent about 2% of the human genome. Exons are captured by a type of DNA chip, after which they can be isolated and sequenced. After sequencing, functional variants can be identified and validated through a variety of complex biological and computer-based technologies. This method is generally carried out on several hundred subjects and controls

While exome sequencing is a very powerful tool for identifying rare variants responsible for disease, it cannot be used to find those that reside in the remaining 98%, the part of the human genome – the so-called non-coding regions (but euphemistically referred to as “junk DNA”). In fact, non-coding DNA contains important genetic information needed for normal cell growth and development. It is widely believed that a substantial proportion of rare variants responsible for bipolar disorder will be found within non-coding DNA,” and the only way to identify them is by whole genome sequencing – the complete deciphering of an individual’s entire genetic makeup.

The capacity to sequence an entire genome has been made possible by breath-taking advances in sequencing technology. About 11 years ago the entire sequence of a human’s DNA was published – which was accomplished by an international consortium that spent more than a decade on the project at a cost of $3-billion ($1/base). Recent advances, however, have reduced the time it takes to sequence a genome to a couple of months, and have brought the cost down to ~$5,000, making it economically feasible to use it as a tool to find rare variants throughout the entire human genome; exons and non-coding regions. However, the biological and computational tools needed to sift through the entire genome to find the precise disease-causing mutation responsible for a disorder in a person is much more daunting than exome sequencing.

Whole genome sequencing is ideal for identifying rare disease-causing mutations in families with multiple affected members. In this scenario, we would expect to find the same rare, disease-causing variant in all affected members, assuming the illness has been transmitted from a single parent, greatly simplifying, but by no means eliminating, the difficult computational aspects of whole genome sequencing.

With our very extensive clinical network, we have already identified several families who appear to qualify for whole genome sequencing.

In Summary

JBRF will continue to collect DNA from individuals with pediatric onset bipolar disorder and their parents for a triad-based GWAS to capture common variants. The affected children will also be analyzed by exome sequencing to capture rare variants occurring in exons. Finally, we are recruiting families loaded with bipolar disorder for whole genome sequencing in order to identify rare variants occurring anywhere in the genome.

Research can change lives.

Your donation today will move us closer to accomplishing these sequencing studies. JBRF relies upon your support to continue this very important research.

A child struggling with a bipolar disorder is often highly gifted, but may have difficulty making transitions, and, according to the DSM-IV, would be diagnosed as having co-morbid or co-occuring syndromes that make him or her distractible, inattentive, anxious or very perfectionistic with some obsessive characteristics. He or she may also be sleepy from medications or may be having cognitive difficulties as a result of them. Frequently, children with bipolar disorder have associated learning disabilites and executive function deficits which make it extremely difficult for them to organize and break things down and accomplish complex tasks (we will discuss these executive function deficits in more detail).

All of these co-morbid conditions, medication issues, known and unknown learning disabilities and organizational deficits complicate a student’s acquisition of knowledge and adjustment to academic demands.

When one also considers that these children have an illness which causes their ability to focus and energy levels to wax and wane (often according to the season) it’s not hard for parents and educators to realize these children need special accommodations in school.

In creating the type of education you want for your son or daughter, you must keep in mind that although all the children we are discussing here have bipolar disorder, each child is an individual with different social, emotional, and academic strengths and weaknesses. Therefore, their educational needs may vary from one season or school year to the next.

The JBRF Educational Page is intended to help parents, teachers and the educational team ease the strain for the child struggling with these issues and to ensure a comfort level that allows these students to learn, benefit, and excel in the academic environment.

A targeted treatment for children struggling with bipolar disorder.

JBRF received approval from the U.S. Food and Drug Administration (“FDA”) to begin the clinical trial of a pharmaceutical agent to treat the symptoms of bipolar disorder in children.

The clinical trial will study the efficacy and safety of the use of intranasal ketamine in the treatment of children ages 6-12 with bipolar disorder and an identifiable biological marker associated with body temperature dysregulation.

This FDA approval is especially noteworthy because, whereas ketamine has been studied as a treatment for depression in adults, this will be the first time ketamine will be tested as a treatment option for bipolar disorder in children. JBRF is sponsoring the first placebo-controlled study to apply this novel treatment in this age group.

Ketamine may prove to have the most positive impact on a unique set of behavioral, cognitive and physiological characteristics associated with a group of children who are the most resistant to traditional treatments and suffer repeated hospitalizations.

Finding the genetic basis of pediatric onset bipolar disorder has long been part of the mission of the JBRF.

Over the past decade there have been extraordinary technological advances made in identifying genes involved in a host of neuropsychiatric disorders, including adult forms of bipolar disorder, schizophrenia, autism, and ADHD, among others. Identifying the underlying genetic basis for such complex traits is quite difficult, and geneticists have had to rely on several different strategies, each requiring their own unique patient/family population.

Large multi-generation families with many affected members were needed for the earliest type of genetic analysis. The next strategy required affected sibling pairs, then family trios (mother, father and affected child). More recently, individual cases (thousands of them) have been needed. The newest technique – arguably the most challenging genetic strategy of all – is a very in-depth survey of the human genome that will require (going back full circle) the recruitment of families with many affected individuals. This could include multiple siblings with bipolar disorder, as well as their affected parents, grandparents, cousins, uncles and aunts.

On December 15th, the Lattner Family Foundation, Inc. granted JBRF $170,000 to undertake such a study with the goal of identifying the gene or genes suspect in early onset bipolar disorder.

This study will be undertaken in conjunction with various members of the JBRF research consortium. The genes will be sequenced at the Laboratory of Behavioral Genetics at the Albert Einstein College of Medicine under the supervision of Dr. Herb Lachman.

Maplewood, NJ – November 3, 2011The Juvenile Bipolar Research Foundation (“JBRF”) announced today that the Federal Drug Administration (“FDA”) has approved its submission of a request to study the use of intranasal ketamine in the treatment of children ages 6-12 with bipolar disorder who also have an identifiable biological marker associated with body temperature dysregulation. “This research, funded by donations from supporters of JBRF, will be the first placebo-controlled study to apply this novel treatment in this age group “ said Inger Sjogren, Executive Director of the JBRF.Dr. Demitri Papolos, Director of Research of the JBRF, noted that a controlled study of ketamine using, for the first time, an intranasal form of administration will build upon previous work performed in both children and adults. A pilot study that he and his colleagues have conducted with over 30 children who struggle with bipolar disorder and are resistant to traditional treatments has already shown great promise using this approach. In many cases, full resolution of symptoms in the most severe form of the disorder has been observed. This work is consistent with findings from studies in adults with treatment resistant depression who received a single dose of ketamine given intravenously.Ketamine may prove to have the most positive impact on a unique set of behavioral, cognitive and physiological characteristics associated with a group of children who are the most resistant to traditional treatments and suffer repeated hospitalizations. Dr. Papolos and his colleagues first reported on the specific behavioral attributes in this group, termed Fear of Harm, in the Journal of Affective Disorders in 2009. Since that time, a specific biological marker has been attributed to this severe subtype of the illness in children. This marker, associated with a dysregulation of body temperature will be further studied with the use of a novel monitor designed to collect a wide range of physiological signals related to temperature and sleep.Ms. Sjogren said that the study was expected to begin within the next 3 months and last approximately 12 months. Further information is available at http://www.jbrf.org.The JBRF is a 501(c)(3) corporation founded to support research into the study and treatment of bipolar disorder in children and adolescents.

For information regarding the JBRF and its mission please contact Executive Director Inger Sjogren at ingersjogren@jbrf.org.